6-(4-Methylpiperazino)-4,5-dihydrothieno[2,3-c]acridine (LS-342) is essentially non-toxic in PBM and Vero cells at concentrations greater than 100 micromoles and active against HIV-1 in human PBM cells infected with HIV-1 (strain LAV-1) at the concentration of 2 micromoles. Several unfused analogs of LS-342 are also active at the 1 micromole concentration level. Based on the preliminary QSAR analysis, DNA binding studies, RNA binding studies, negative results of the attempted inhibition at both viral RT and protease with the active compounds, a working hypothesis has been formulated that active heteropolyaromatic compounds of this class interact with the viral RNA. More specifically, the proposed research is based on the working hypothesis that the active compounds recognize a specific conformation of the RNA in gene control region of the HIV-1 genome due to the presence of unusual structural features such as base bulges or loops of bases. A rational approach is proposed to developing novel heteropolyaromatic anti-HIV-1 agents of high activity (strong and specific binding to the viral RNA) and low cell toxicity (negligible binding to host DNA). This problem will be attacked by designing molecules with the structural features that are known to increase binding of these molecules with RNA and/or decrease their binding with DNA. The heteropolyaromatic molecules proposed for the development as anti-HIV-1 agents contain intrinsically twisted, fused ring systems or unfused ring systems that can attain the twisted conformation. The molecular twist does not prevent complex formation of the molecule with bulges or loops of base regions on the RNA but strongly discourages the formation of a stable complex with DNA. Anionic or potentially anionic substitutent will be attached to the heteroaromatic systems of these molecules. Such substituents, when properly positioned, strongly stabilize the complex with RNA but, in general, destabilize the interaction of the substituted molecules with DNA. The molecules will also contain cationic groups which stabilize the interaction with nucleic acids. A proper chirality will be introduced at these groups to discourage complex formation with DNA. The rules of the dipole moment orientation in the aromatic molecules for their interaction with nucleic acids, recently developed in this laboratory, will also aid in this research. Finally, bifunctional molecules, RASORS, will be synthesized in collaboration with Project 3. RASORS will be highly specific for the viral RNA. The design and synthesis work will be guided by QSAR analyses.